This proposal is a response to the National Institute of Aging Pilot Research Grant Program PA-99-049 on Cardiovascular and Cerebrovascular Aging. Age represents a major risk factor for the development of vascular diseases. Vascular response to injury is far more pronounced in aging mammals than in young ones. It is unclear whether this exaggerated vascular response to injury is a consequence of senescence intrinsic to vascular cells, or a phenotype change that adapts to the aging environment. The overall goal of this proposal is to delineate factors that are responsible for the exaggerated vascular response to injury associated with aging. Specifically, in AIM I we will determine whether the exaggerated vascular response to injury is due to the intrinsic property of the aging vessel or due to the aging milieu. We will determine whether vascular response to injury can be attenuated when mechanically injured (with a balloon catheter) aging aortas ( from 30 months old rats) are "parked" (transplanted) for a period of time in young (6 months old) syngeneic recipients. Conversely, injured aortas from young donors will be parked into aging recipients to assess whether the vascular response is accelerated in the aging milieu external to the vessel. In AIM II, we will determine if there is a difference in the molecular and biomechanical properties of the young and aging vessels, and whether these properties are affected by the aging milieu. Key markers associated with vascular remodel (insulin-like growth factor [IGF]-I receptor, metalloproteinase [MMP]-2, estrogen receptors-alpha and beta) and biomechanical parameters (force, action potential, calcium flux) of the young and aging vessels will be compared under different "parking" experiments (as in Aim I). Lastly, in AIM III, we will determine the effects of estrogen on the response to injury in young and aging vessels. If the response to injury is accelerated in young aortas transplanted in post-menopausal female recipients, we determine if and how estrogen supplementation attenuates this response. Findings from this study will help design better strategies to prevent and to treat aging-related vascular diseases.